This invention relates to a novel process for preparing hydroxyphenylglycine compounds of the formula: ##STR3## wherein n is an integer of one to three.
Hydroxyphenylglycine compounds (I) of the invention are useful as intermediates in the synthesis of penicillins and cephalosporins.
It is known that hydroxyphenylglycine compounds may be prepared by condensation of a hydroxybenzaldehyde, sodium cyanide and ammonium bicarbonate to give the corresponding hydroxybenzylhydantoin. This procedure is followed by hydrolysis with sodium hydroxide. It is also known that hydroxyphenylglycine compounds may be obtained by the Strecker synthesis (i.e., condensing a hydroxybenzaldehyde and ammonium cyanide, and then hydrolyzing the resultant hydroxybenzylaminonitrile with hydrochloric acid). However, the hydroxybenzaldehyde employed as one of the starting materials therein is too expensive for practical use in large scale production of hydroxyphenyglycine compounds. In addition, since the hydrolysis step of these known methods are conducted at a high temperature such as 100.degree. to 120.degree. C. for a long period of time (e.g., 4 to 40 hours), the intermediate and final products thereof tend to cause partial decomposition during the hydrolysis step if the hydroxy group thereof has not been protected beforehand.
In addition to the above-mentioned methods, British Pat. Nos. 1353612 and 1371896 disclose the preparation of hydroxyphenylglcine compounds by condensing glyoxylic acid with ammonia and phenol. However, since this method is usually carried out under alkaline conditions by using an excess amount of concentrated ammonia and phenol, undesirable resinous products are obtained during the reaction and additional steps are required to remove the resulting contaminants. Moreover, this method results in the formation of an ammonium salt of hydroxyglycine [HOCH.sub.2 (NH.sub.2)COONH.sub.4 ]and the condensation product (i.e., the hydroxyphenylglycine compound) is always obtained in the form of a water-soluble ammonium salt. Therefore, the isolation and recovery of the highly pure hydroxyphenylglycine compound as the free acid is only possible by resorting to the costly and time consuming steps of (1) extracting excess phenol with a solvent; (2) distilling the reaction solution to remove ammonia; (3) neutralizing the reaction solution with concentrated hydrochloric acid; and (4) again neutralizing the resultant hydrochloride with ammonia to liberate the free hydroxyphenylglycine compound.
As a result of our investigations we have discovered a novel method for the production of hydroxyphenylglycine compounds. This method results in the precipitation of crystals of the free acid form of the hydroxyphenylglycine compounds as the reaction proceeds. Thus, highly pure hydroxyphenylglycine compounds can be readily recovered by simply filtrating the reaction solution.
This method is accomplished by condensing glyoxylic acid or one of the salts of glyoxylic acid and phenol and an ammonium salt of an organic or inorganic acid under neutral or acidic conditions. Thus, an object of the present invention is to provide a practical and economical process for the industrial scale production of hydroxyphenylglycine compounds. Another object of the invention is to provide a method which makes it possible to prepare highly pure free hydroxyphenylglycine compounds without purification techniques required in prior art methods. Another object is to provide a method of preparing said compounds without using an excess of concentrated ammonia. Additional objects of the present invention will be clearly observed from the following description.